PAARH suppresses Kupffer cell phagocytosis to promote tumor liver metastasis by upregulating CD47

Metastasis is the primary cause of cancer-related mortality, with the liver being a common metastatic target organ for multiple malignancies. Kupffer cells (KCs), the liver-resident macrophages, play a crucial role in suppressing liver metastasis by phagocytosing disseminated tumor cells. However, the molecules modulating KC phagocytosis and liver metastatic progression remain poorly understood. Our previous work identified PAARH as an oncogenic factor in hepatocellular carcinoma (HCC) that correlates with poor patient prognosis. Here, we demonstrate that PAARH functions as an anti-phagocytic molecule for KCs. PAARH facilitates liver metastasis of various tumor cells by suppressing KCs phagocytosis. In vitro phagocytosis assays showed that PAARH suppresses the phagocytosis of tumor cells cultured under hypoxia by KCs. Mechanistically, PAARH recruits HIF-1α to the CD47 promoter, activating CD47 transcription under hypoxia. Consistent with this, PAARH and HIF-1α expression positively correlate with CD47 levels across multiple human tumor tissues. CD47 was identified as a phagocytosis checkpoint for KCs, mediating PAARH’s effects on phagocytosis inhibition and liver metastasis. Clinically, high PAARH and CD47 expression in tumors were associated with increased liver metastases. Our findings establish PAARH as a critical anti-phagocytic molecule for KCs through transcriptional activation of CD47 and suggest that targeting PAARH could selectively enhance the clearance of hypoxic tumor cells, offering a potential therapeutic strategy to limit liver metastasis.